It has been suggested that generic iron complex formulations
could have higher levels of labile iron, leading to the formation of a
greater amount of non-transferrin bound iron (NTBI) in vivo than the reference
listed drug (RLD) that would potentiate oxidative stress and inflammation,
then resulting in direct cellular damage. The objectives of this study are
to evaluate various in-vitro methods of determining labile iron in the
parenteral iron complex formulations and develop a bio-relevant in-vitro
method to predict the amount of NTBI in vivo. Such a predictive in-vitro
method will allow for linkage of FDA's equivalence standards to in vivo
performance.

Key Dates

Posted Date

April 2, 2013

Open Date (Earliest Submission Date)

April 15, 2013

Letter of Intent Due Date(s)

Not Applicable

Application Due Date(s)

May 24, 2013, by 11:59 PM Eastern Time.

Applicants should be aware that on-time submission means
that an application is submitted error free (of both Grants.gov and eRA
Commons errors) before 11:59 p.m. Eastern Time on the application due date. Applicants
are encouraged to apply early to allow adequate time to make any corrections
to errors found in the application during the submission process by the due
date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

June or July 2013

Advisory Council Review

August 2013

Earliest Start Date

September 2013

Expiration Date

June 1, 2013

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed to do otherwise (in
this FOA or in a Notice from the NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA)
is required and strictly enforced. Applicants must read and follow all
application instructions in the Application Guide as well as any
program-specific instructions noted in Section
IV. When the program-specific instructions deviate from those in the
Application Guide, follow the program-specific instructions. Applications that
do not comply with these instructions may be delayed or not accepted for review.

Parenteral iron injection products are used to treat anemia,
particularly in patients with chronic kidney disease (CKD). There are four
types of parenteral iron complex products available in North America: iron
sucrose, sodium ferric gluconate, iron dextran, and ferumoxytol. All
parenteral iron products are colloids comprising a continuous aqueous medium
and particles of carbohydrate protected iron oxyhydroxide.

After intravenous administration, iron colloid particles are
processed by phagocytes and iron ions are delivered to the lysosomes within the
cell as part of the intracellular labile iron pool. The phagocyte uptake and
biodistribution of iron complex particles depend upon their physicochemical
properties. If iron is not needed immediately, it is stored in the form of
ferritin or hemosiderin. When the iron is needed in the body, iron is released
from the cell and transferrin binds iron ions and delivers them to their destination.
If transferrin is oversaturated or if the iron complex product is so unstable
that iron is spontaneously released at a rate that exceeds transferrin binding
capacity, non-transferrin bound iron (NTBI) is formed in the plasma. NTBI can
be toxic to cells as it acts as a catalyst in the formation of free radicals
from reactive oxygen species.

In March 2011, FDA approved the first generic sodium ferric
gluconate iron complex Nulecit™, an alternative to Ferrlecit®. It has been
suggested (in a March 2011 EU guidance) that generic iron formulations could have
higher levels of labile iron, leading to the formation of a greater amount of
nontransferrin-bound iron (NTBI) in vivo than the RLD that would potentiate
oxidative stress and inflammation, then resulting in direct cellular damage and
possibly increasing the risk of atherosclerotic disease. FDA's approval of
generic iron complex products was based on equivalence in product
characteristics supported by equivalence in in vivo pharmacokinetic studies. Products
that meet these approval standards should have no significant difference in
NTBI. The March 2011 EU guidance reflects the fact that the EU equivalence
approach recommends non-clinical studies, unlike the FDA approach, which sets
strict standards for product characteristic equivalence.

Currently there are several in vitro methods available to
determine the amount of labile iron in the parenteral iron injection including
ultra-filtration, measurement of Fe reduction, catalytic bleomycin assay, and
in vitro haemodialysis. However, their ability to predict the formation of
NTBI in vivo has not been evaluated. A bio-relevant in-vitro method to
determine labile iron in the iron complex product should be developed to help
predict the amount of NTBI in vivo. If a predictive in vitro method were
developed, it would allow for linkage of FDA's equivalence standards to in vivo
performance (providing more freedom in formulation characteristics) or possibly
support a reduction of in vivo equivalence studies.

Objectives

The objectives of this study are to evaluate various
in-vitro methods of determining labile iron in the parenteral iron complex
product formulation and develop a bio-relevant in-vitro method to predict the
amount of NTBI in vivo. Such a predictive in-vitro method will allow for
linkage of FDA's equivalence standards to in vivo performance.

Detailed Descriptions

The project will involve the following:

In-vitro
study

1. Formulation study – A series of iron complex formulations
which have different amount of labile iron are manufactured. Formulations will
be fully characterized in terms of molecular weight, particle size
distribution, iron oxide crystalline structure, iron environment, carbohydrate
shell, and etc.

2. Evaluation of labile iron – Different in-vitro methods,
including but not limited to ultra-filtration, catalytic bleomycin assay, measurement
of Fe reduction, in vitro haemodialysis will be evaluated to determine the
amount of labile iron in the above iron complex formulations.

In-vivo
study

3. Pharmacokinetic study in preclinical species –
Pharmacokinetic studies with the above iron complex formulations in preclinical
species will be conducted by assessing total iron, transferrin-bound iron, and
non-transferrin bound iron.

2 Burkitt MJ, et al. A simple, highly sensitive and improved
method for the measurement of bleomycin-detectable iron: the 'catalytic iron
index' and its value in the assessment of iron status in haemochromatosis. Clin
Sci (Lond). 2001 Mar;100(3):239-47.

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there
will be substantial Federal scientific or programmatic involvement.
Substantial involvement means that, after award, FDA scientific or program
staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New

The OER
Glossary and the SF424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon FDA appropriations
and the submission of a sufficient number of meritorious applications.

FDA/CDER intends to fund up to 1 award, corresponding up
to $500,000 total costs, for fiscal year 2013.

Award Budget

Awards are contingent upon the availability of funds.
Budgets should not exceed $500,000 in total costs.

Award Project Period

Maximum project period is one (1) year.

FDA grants policies as
described in the HHS Grants
Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for FDA support as Public or Private
Institutions of Higher Education:

Applicant organizations must complete and maintain the
following registrations as described in the SF 424 (R&R) Application Guide
to be eligible to apply for or receive an award. All registrations must be
completed prior to the application being submitted. Registration can take 6
weeks or more, so applicants should begin the registration process as soon as
possible. Failure to complete registrations in advance of a due date is not a
valid reason for a late submission.

Dun and Bradstreet
Universal Numbering System (DUNS) - All registrations require that
applicants be issued a DUNS number. After obtaining a DUNS number, applicants
can begin both SAM and eRA Commons registrations. The same DUNS number must be
used for all registrations, as well as on the grant application.

System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least
annually. The renewal process may require as much time as the
initial registration. SAM registration includes the assignment of a Commercial
and Government Entity (CAGE) Code for domestic organizations which have not
already been assigned a CAGE Code.

eRA Commons - Applicants
must have an active DUNS number and SAM registration in order to complete the
eRA Commons registration. Organizations can register with the eRA Commons as
they are working through their SAM or Grants.gov registration. eRA Commons
requires organizations to identify at least one Signing Official (SO) and at
least one Program Director/Principal Investigator (PD/PI) account in order to
submit an application.

Grants.gov – Applicants
must have an active DUNS number and SAM registration in order to complete the
Grants.gov registration.

All PD(s)/PI(s) must have an eRA Commons account and should
work with their organizational officials to either create a new account or to
affiliate an existing account with the applicant organization’s eRA Commons
account. If the PD/PI is also the organizational Signing Official, they must
have two distinct eRA Commons accounts, one for each role. Obtaining an eRA
Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for FDA support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

FDA will not accept any application that is essentially the
same as one already reviewed within the past twelve months, except for
submission:

To an RFA of an application that was submitted previously as an
investigator-initiated application but not paid;

Of an investigator-initiated application that was originally
submitted to an RFA but not paid; or

Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

All page limitations described in the SF424 Application
Guide and must be followed, with the following exception:

For this specific FOA, the Research Strategy section is limited
to 50 pages.

Required and Optional Components

The forms package associated with this FOA includes all
applicable components, required and optional. Please note that some components
marked optional in the application package are required for submission of
applications for this FOA. Follow all instructions in the SF424 (R&R)
Application Guide to ensure you complete all appropriate “optional” components.

SF424(R&R) Cover (Required)

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Project/Performance Site Locations
(Required)

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Other Project Information (Required)

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Senior/Key Person Profile (Required)

All instructions in the SF424 (R&R) Application Guide
must be followed.

R&R Budget (Required)

All instructions in the SF424 (R&R) Application Guide
must be followed with the following modifications:

If an applicant is requesting indirect costs as part of their
budget, a copy of the most recent Federal indirect cost rate or F&A
agreement must be provided as part of the application submission. This
agreement should be attached to the RESEARCH & RELATED Other Project
Information Component as line #12 'Other Attachments'.

PHS 398 Cover Letter (Optional)

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Cover Page Supplement (Required)

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Research Plan (Required)

All instructions in the SF424 (R&R) Application Guide
must be followed.

Resource
Sharing Plan: Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs
requested for any one year, should address a Data Sharing Plan.

Appendix: Do not use the Appendix to circumvent page limits. Follow all
instructions for the Appendix as described in the SF424 (R&R) Application
Guide.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies
described in the HHS Grants
Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications
before the due date to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the
status of the application in the eRA Commons, FDA’s electronic system for grants
administration. eRA Commons and Grants.gov systems check the application
against many of the application instructions upon submission. Errors must be
corrected and a changed/corrected application must be submitted to Grants.gov
on or before the application due date. If a Changed/Corrected application is
submitted after the deadline, the application will be considered late. Late
applications will not be accepted for this announcement.

Applicants
are responsible for viewing their application before the due date in the eRA
Commons to ensure accurate and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

No awardee or performance site institution may spend funds
on human subject research or enroll subjects until documentation of IRB
approval for the IRB of record is on file with the FDA grants management
office.

6. Other Submission
Requirements and Information

Applications must be submitted electronically following the
instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the
SF424(R&R) Application Package. Failure to register in the Commons
and to include a valid PD/PI Commons ID in the credential field will prevent
the successful submission of an electronic application to FDA. See Section III of this FOA for information on
registration requirements.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the System for Award Management. Additional information may be
found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the assigned Grants Management Specialist and responsiveness by components of participating organizations,
FDA. Applications that are incomplete and/or nonresponsive will not be
reviewed.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in
any year (excluding consortium F&A) must contact FDA program staff at least 6 weeks before
submitting the application and follow the Policy on the Acceptance for Review
of Unsolicited Applications that Request $500,000 or More in Direct Costs as
described in the SF424 (R&R) Application Guide.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the objective review process.

Overall Impact

Reviewers will provide an overall impact score to reflect
their assessment of the likelihood for the project to exert a sustained,
powerful influence on the research field(s) involved, in consideration of the
following review criteria and additional review criteria (as applicable for the
project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD/PI, do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact score, but will not give
separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

All applications determined to be complete and responsive
will undergo an objective review process. An objective review panel will
evaluate complete and responsive applications according to the criteria listed
in the Scored Review Criteria section above.

As part of the objective review, all applications:

Will receive a written critique.

Appeals of initial objective review will not be accepted for applications submitted in
response to this FOA.

Applications will be ranked on the basis of their Composite
Score and will compete for available funds with all other recommended
applications. Following the objective review, recommended applications will
receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by objective review.

If the application is under consideration for funding, FDA
will request "just-in-time" information from the applicant as
described in the HHS Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to the DUNS, SAM
Registration, and Transparency Act requirements as noted in the HHS Grants
Policy Statement.

Additional terms and conditions regarding FDA regulatory and
Programmatic requirements may be part the Notice of Award.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and FDA grant administration policies.

The administrative and funding instrument used for this program will be the
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial FDA programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the FDA purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume direction,
prime responsibility, or a dominant role in the activities. Consistent with
this concept, the dominant role and prime responsibility resides with the
awardees for the project as a whole, although specific tasks and activities may
be shared among the awardees and the FDA as defined below.

The
PD(s)/PI(s) will have the primary responsibility for:

Awardees will retain custody of and have primary rights to the
data and software developed under these awards, subject to Government rights of
access consistent with current DHHS, PHS, and FDA policies.

FDA
staff will have substantial programmatic involvement that is above and beyond
the normal stewardship role in awards, as described below:

Participate in developing a study protocol;

Participate in data analysis;

Review method validation;

Review and conduct quality assurance of results;

Participate in writing manuscripts for publication;

Additionally, an agency program official or program director will
be responsible for the normal scientific and programmatic stewardship of the
award and will be named in the award notice.

Areas
of Joint Responsibility include:

None; all responsibilities are divided between awardees and FDA
staff as described above.

3. Reporting

When multiple years are involved, awardees will be required
to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR)
and financial statements as required in the HHS Grants
Policy Statement and the terms and conditions of the Notice of Award.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the HHS Grants
Policy Statement and the terms and conditions of the Notice of Award.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable FDA grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the HHS Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.